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Long Chain Hydroxyacyl-CoA Dehydrogenase Deficiency

Isl long Ch Hyd Ac Coa Deh Def


Presentation

  • The mean age of clinical presentation was 5.8 months (range: 1 day-26 months). Seven (15%) of the patients presented in the neonatal period.[pediatrics.aappublications.org]
  • We used single-stranded conformation variance analysis of the exons of the human LCHAD (α subunit) gene to determine the molecular basis of LCHAD deficiency in three families with children presenting with sudden unexplained death or hypoglycemia and abnormal[uthscsa.influuent.utsystem.edu]
  • These long chain defects have variable presentations, they may present in the neonate or infant with sudden death, hepatopathy (Reyes disease), hypoketotic hypoglycaemia, rhabdomyolysis, myopathy, cardiomyopathy and with late complications such as peripheral[pediatricfocus.wordpress.com]
  • The variable presentation includes infantile hypoketotic hypoglycemia, vomiting, lethargy, hypotonia, and failure to thrive.[genedx.com]
HELLP Syndrome
  • However, mothers pregnant with babies homozygous for the deficiency often have problems including anorexia, vomiting, abdominal pain, and jaundice during the third trimester of pregnancy (HELLP syndrome).[emilytam.com]
  • Clin Chem 52:530–534 CrossRef PubMed den Boer ME, Ijlst L, Wijburg FA et al. (2000) Heterozygosity for the common LCHAD mutation (1528 G   C) is not a major cause of HELLP syndrome and the prevalence of the mutation in the Dutch population is low.[springermedizin.de]
  • The mother seems an unlikely source because this would imply that HELLP syndrome and AFLP should occur in metabolically stressed nonpregnant female and male heterozygotes.[nature.com]
  • (PMID: 7918661) Zhang QX … Baldwin GS (Biochimica et biophysica acta 1994) 2 3 4 22 60 Neither maternal nor fetal mutation (E474Q) in the alpha-subunit of the trifunctional protein is frequent in pregnancies complicated by HELLP syndrome.[genecards.org]
  • syndrome Treatment: Avoidance of fasting; high-carbohydrate diet; carnitine; medium-chain triglycerides; during acute episodes, high-dose glucose For retinopathy, docosahexanoic acid possibly useful Mitochondrial trifunctional protein (TFP) deficiency[merckmanuals.com]
Fatigue
  • If fatigue or muscle pain ensues, rest, extra fluid and carbohydrate-containing snacks are encouraged.[gmdi.org]
  • The first symptoms of hypoglycemia are: extreme sleepiness or fatigue weakness nausea vomiting irritability or jitteriness behavior changes If hypoglycemia is not treated, a child with LCHADD can develop: breathing problems swelling of the brain seizures[newbornscreening.info]
  • These patients have hypoketotic hypoglycemia, hepatomegaly, recurrent “infections”, and easy fatigue resulting in recurrent sore muscles. Some present with exercise-induced rhabdomyolysis.[genico.ch]
Sudden Infant Death Syndrome
  • In the past, LCHADD was not often diagnosed until a baby was very sick or after they passed away from apparent Sudden Infant Death Syndrome (SIDS). Now testing at birth (newborn screening) happens in all states in the United States for LCHADD.[thinkgenetic.com]
  • Fatty liver is noted at autopsy, often leading to a misdiagnosis of Reye’s syndrome or Sudden Infant Death Syndrome (SIDS) in an infant.[genico.ch]
Anorexia
  • However, mothers pregnant with babies homozygous for the deficiency often have problems including anorexia, vomiting, abdominal pain, and jaundice during the third trimester of pregnancy (HELLP syndrome).[emilytam.com]
Respiratory Insufficiency
  • Olsen RKJ, Pourfarzam M, Morris AAM, Dias RC, Knudsen I, Andresen BS , Gregersen N, Olpin SE (2004) Lipid storage myopathy and respiratory insufficiency due to ETFQO mutations in a patient with late-onset multiple acyl-CoA dehydrogenation deficiency.[findresearcher.sdu.dk]
  • Neurologic episodes of painful paresthesias, weak- ness, paralysis, and respiratory insufficiency occur. There is a high risk for development of hepatic nodules and hepatocellular carcinoma. Most untreated patients die in infancy or early childhood.[genico.ch]
Failure to Thrive
  • LCHAD deficiency is usually diagnosed in infancy or early childhood, when the affected individual presents with symptoms such as vomiting, low blood sugar, lack of energy, muscle weakness, liver problems, and failure to thrive.[nxgenmdx.com]
  • Eleven patients (22%) presented with chronic problems, consisting of failure to thrive, feeding difficulties, cholestatic liver disease, and/or hypotonia.[pediatrics.aappublications.org]
  • The variable presentation includes infantile hypoketotic hypoglycemia, vomiting, lethargy, hypotonia, and failure to thrive.[genedx.com]
  • […] to thrive Faltering weight Weight faltering [ more ] 0001508 Feeding difficulties Feeding problems Poor feeding [ more ] 0011968 Generalized hypotonia Decreased muscle tone Low muscle tone [ more ] 0001290 Intellectual disability Mental deficiency Mental[rarediseases.info.nih.gov]
Hydrops Fetalis
  • Stay at the forefront of your field thanks to new and completely revised chapters covering topics such as: Principles and Practice l Immune and Non-immune Hydrops Fetalis l Amniotic Fluid Volume l Enhancing Safe Prescribing in the Neonatal Intensive Care[books.google.com]
Progressive Loss of Vision
  • Clinical The major clinical problem in these patients is a slowly progressive loss of vision leading to blindness, usually by the fifth decade of life.[genico.ch]
Muscle Hypotonia
  • These problems include problems eating, lack of energy (lethargy), low blood sugar (hypoglycemia), weak muscles (hypotonia), liver problems, and eye problems (retina).[thinkgenetic.com]
  • The picture of methymalonic acidemia as recurrent vomiting, dehydration, respiratory distress, muscle hypotonia, and lethargy that can lead to coma and death is often seen in the first week of life. Metabolic acidosis is pronounced.[genico.ch]
Muscular Atrophy
  • He is currently involved in multiple clinical trials of novel genetic interventions for the treatment of spinal muscular atrophy and Duchenne muscular dystrophy.[books.google.com]
Muscle Spasm
  • Symptoms of a LCHAD or TFP metabolic crisis include: poor feeding vomiting excessive sleepiness irritability muscle spasms enlarged liver If a metabolic crisis is not treated, breathing problems, seizures, coma, brain damage and sometimes death can occur[newbornscreening.on.ca]
Psychomotor Retardation
  • Even treated, there can be psychomotor retardation. Relevant reading : Info from FODSupport.org Den Boer MEJ, Wanders RJA, Morris AAM, et al . (2002).[emilytam.com]
  • Infants who are diagnosed and treated still have a risk for psychomotor retardation.[emedicine.medscape.com]
  • Psychomotor retardation is a life-long complication. Some patients have first presented later in infancy with encephalopathy and associated ketoacidosis, or developmental delay.[genico.ch]
Hematuria
  • The patient may be hypoglycemic with fasting and have metabolic acidosis, elevated liver enzymes with hepatomegaly (due to steatosis), cholestasis, hypertrophic cardiomyopathy, proteinuria, and hematuria.[genico.ch]
Confusion
  • Sometimes this condition is confused with Reye syndrome - see Reye 's syndrome -. This process is due to mutations in the gene HADHA, located on the short arm of chromosome 2 (2p23).[ivami.com]
  • Muscle pathology can easily be confused with respiratory chain disorders. Enzyme assays also may show dysfunction of some of the respiratory chain complexes, possibly due to accumulation of toxic intermediates from mitochondrial beta-oxidation.[emilytam.com]
  • Differential Diagnosis The infant form may be confused with other rare forms of cardiomyopathy, including glycogen storage disease type 2 (Pompe disease), VLCAD and multiple acyl-CoA dehydrogenase deficiency, and other carnitine disorders, such as carnitine-acylarnitine[medicalhomeportal.org]
Delayed Milestone
  • Symptoms are progressive spastic paraplegia, failure to thrive, delayed milestones, hyperactivity and irritability, with episodic vomiting, hyperammonemia and seizures. Mental retardation is a result of cerebral atrophy which leads to microcephaly.[genico.ch]
Neonatal Hypotonia

Workup

  • Workup of such patients includes measuring plasma amino acids and looking for succinylacetone on urine organic acid analysis.[genico.ch]
Hypoketotic Hypoglycemia
  • Treatment : It is important to avoid fasting to prevent hypoketotic hypoglycemia. A low fat, high carbohydrate diet, MCA oils, essential oil supplementation (linoleic and linolenic acid) and carnitine have been used for treatment.[emilytam.com]
  • Thirty-nine patients (78%) presented with hypoketotic hypoglycemia, the classical features of a fatty acid oxidation disorder.[pediatrics.aappublications.org]
  • It presents during infancy or early childhood, and is characterized by hypoketotic hypoglycemia, cardiomyopathy, hypotonia, and hepatomegaly.[cags.org.ae]
  • The variable presentation includes infantile hypoketotic hypoglycemia, vomiting, lethargy, hypotonia, and failure to thrive.[genedx.com]
Fasting Hypoglycemia
  • hypoglycemia, myopathy, sudden death Treatment: Similar to that for LCHAD deficiency α -Subunit HADHA (2p23)* β -Subunit HADHB (2p23)* MCAD ACADM (1p31)* Biochemical profile: Elevated saturated and unsaturated C8–C10 acylcarnitine esters; elevated urinary[merckmanuals.com]
Liver Biopsy
  • The activity of CPS can be measured in a liver biopsy. Mutation analysis of the CPS gene may be useful for prenatal diagnosis in future pregnancies.[genico.ch]

Treatment

  • Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop. J Inherit Metab Dis. 2009 Aug;32(4):498-505. Published data on treatment of fatty acid oxidation defects are scarce.[pediatricfocus.wordpress.com]
  • Treatment Open Treatment for LCHAD and TFP is started as early as possible and is usually life long.[newbornscreening.on.ca]
  • Transport to hospital for further treatment in consultation with pediatric metabolic specialist. Call 501-364-4050 to speak with the Newborn Screening Coordinator. Make sure baby is fed every 3 hours.[archildrens.org]
  • If your baby has certain signs, your baby’s doctor may suggest starting immediate treatment.[babysfirsttest.org]
  • Make informed clinical choices for each patient, from diagnosis and treatment selection through post-treatment strategies and management of complications, with new evidence-based criteria throughout.[books.google.com]

Prognosis

  • Many patients still suffer acute life-threatening events or long-term neuropathic symptoms despite adequate treatment, and newborn screening has not significantly changed the prognosis for these severe phenotypes.[pediatricfocus.wordpress.com]
  • J Inherit Metab Dis 32:488–497 CrossRef PubMed Spiekerkoetter U, Sykut-Cegielska J (2007) Prognosis and treatment of LCHAD deficiency.[springermedizin.de]
  • ., Enocksson, E. and Lindeberg, L. 3-Hydroxydicarboxylic aciduria — a fatty acid oxidation defect with severe prognosis. J. Pediatr. 116 (1990) 387–392 PubMed CrossRef Google Scholar Hale, D. E. and Thorpe, C.[link.springer.com]
  • However, treatment may improve the long-term prognosis. Conventional therapy may not be sufficient to prevent ophthalmological changes; however, early diagnosis and adequate therapy may delay the progression of retinal complications.[emedicine.medscape.com]
  • You can help by adding to it. ( February 2017 ) Prognosis [ edit ] A 2001 study followed up on 50 patients.[en.wikipedia.org]

Etiology

  • The etiology of the severe peripheral neuropathy of trifunctional protein deficiency may result from the unique metabolite, 3-keto-acyl-CoA, after conversion to a methylketone via spontaneous decarboxylation.[emedicine.medscape.com]
  • This infant had concurrent HIV infection, so that it was difficult to define the etiology of the liver disease, although the introduction of a low-fat diet resulted in a marked improvement in the child’s clinical status.[nature.com]
  • The etiology in 70 to 80% of the non-familial cases is unknown.[genico.ch]

Epidemiology

  • "Medium chain acyl-CoA dehydrogenase deficiency human genome epidemiology review". Genet Med 1 (7): 332–9. PMID 11263545.[en.academic.ru]
  • Relevant External Links for HADHA Genetic Association Database (GAD) HADHA Human Genome Epidemiology (HuGE) Navigator HADHA Atlas of Genetics and Cytogenetics in Oncology and Haematology: HADHA No data available for Genatlas for HADHA Gene Structures[genecards.org]
  • Chronic hemolytic anemia and delayed CNS myelination have also been reported. [9] Epidemiology Frequency United States The incidence of isolated LCHAD activity deficiency and trifunctional protein deficiency is unknown in the United States.[emedicine.medscape.com]
  • Besides epidemiological data (Table 1 ), we evaluated: growth, short and long-term complications, number of hospital admissions and length of stay (in days per year); creatine kinase concentrations (peak levels) as a marker for rhabdomyolysis, and two[ojrd.biomedcentral.com]
  • Population and epidemiology information point to G6PD deficiency as providing some resistance to malaria. Clinical Babies with G6PD deficiency appear normal at birth.[genico.ch]
Sex distribution
Age distribution

Pathophysiology

  • Pathophysiology The molecular defect occurs in the mitochondrial trifunctional protein (MTP).[emedicine.medscape.com]
  • Whether or not the accumulation of long chain acyl carnitines, observed in LCHAD deficiency, are involved in the pathophysiology of the retinal dystrophy is subject to further investigation.[bjo.bmj.com]
  • Pathophysiology Individuals with only one mutation in the genes for MTP (heterozygous) do not come to clinical attention because one normal gene apparently produces enough enzyme activity for catabolizing fatty acids, even in times of metabolic stress[nature.com]
  • The pathophysiology and molecular biology vary among different forms of SCID, however, the lack of T-cell and B-cell function is the common endpoint in all forms of SCID.[genico.ch]

Prevention

  • Screening and treatment aim to prevent metabolic crises and other symptoms and help children with LCHAD and TFP to lead the healthiest lives possible.[newbornscreening.on.ca]
  • ., (LCHAD) (Long Chain hydroxyacyl-CoA dehydrogenase deficiency -LCHAD-) - Gen HADHA Deficiency 3hydroxyacyl-CoA dehydrogenase long chain (LCHAD: Long Chain hydroxyacyl-CoA dehydrogenase deficiency) is a rare disorder that prevents organisms metabolize[ivami.com]
  • During acute illnesses, it may be necessary to admit such a patient for close monitoring and IV glucose to prevent hypoglycemia.[emilytam.com]
  • It prevents the body from properly turning fats into energy. The clinical presentation is highly variable. Symptoms most commonly begin in infancy or early childhood with low blood sugar, lethargy, low muscle tone, liver disease, and heart problems.[sema4genomics.com]
  • Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency is a rare condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting).[ghr.nlm.nih.gov]

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